Noncoding RNAs: Hope and hype at 30 years
Authors: George A. Calin
Journal: Molecular Therapy (2023)

In the 1960s, the RNA World Hypothesis proposed that prebiotic life on Earth arose from RNA. However, it took several decades to unravel the broad spectrum of currently known RNA types. The existence of RNA transcripts without a protein coding function has been known since the 1980s in viruses and bacteria, but the scientific community did not become aware of the existence of such transcripts in eukaryotes until precisely 30 years ago. In 1993, two landmark papers reported the existence of microRNAs in worms; microRNAs are the smallest transcripts identified to date, measuring only 19–21 nucleotides in length.1Lee R.C. Feinbaum R.L. Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993; 75: 843-854https://doi.org/10.1016/0092-8674(93)90529-yAbstract Full Text PDF PubMed Scopus (0) Google Scholar,2Wightman B. Ha I. Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.Cell. 1993; 75: 855-862https://doi.org/10.1016/0092-8674(93)90530-4Abstract Full Text PDF PubMed Scopus (3175) Google Scholar Another decade passed before the involvement of microRNAs in human diseases was confirmed, but once this connection was established, the field grew exponentially. Researchers discovered multiple new noncoding RNA (ncRNA) categories, most of which belong to the large group of long noncoding RNAs (lncRNAs) over 200 nucleotides in length. In this issue of Molecular Therapy, the Editors are pleased to present our avid readers with several excellent reviews focused on topics of interest in the study of ncRNAs, including their practical applications. The field of ncRNAs is expanding and is no longer purely the domain of highly specialized scientists. Therefore, such broad topic special issues are of great interest for a large audience of readers from various medical and non-medical fields. We hope you will enjoy reading this collection and share in our excitement for the future of ncRNA-based biology and therapeutics. With the widespread usage of high-throughput sequencing, the identification of novel transcripts has increased exponentially and revolutionized the way we study diseases. The field of microRNA/ncRNAs produces an impressive 25,000 publications annually. These publications mostly fall into one of four categories: cataloging the hundreds of thousands, if not millions, of lncRNAs codified in the human genome, understanding ncRNA functions in normal cells and diseased cells, developing clinically meaningful biomarkers for early detection or prognosis of diseases where such markers are missing, and the development of new RNA therapeutics based on either targeting lncRNA or using small RNAs as drugs. While the first two topics are fundamental for understanding the roles of ncRNAs in biology and medicine, the discovery of new biomarkers and therapeutics will undoubtedly create a lasting legacy in science. In this issue of Molecular Therapy, Qadir and colleagues present an updated view on the very interesting topic of circular RNA regulation of the crosstalk between inflammation and tumorigenesis.3Qadir J. Wen S.Y. Yuan H. Yang B.B. CircRNAs regulate the crosstalk between inflammation and tumorigenesis: the bilateral association and molecular mechanisms.Mol. Ther. 2022; https://doi.org/10.1016/j.ymthe.2022.12.005Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar In well thought-out examples, the authors focus on the regulatory mechanisms by which circRNAs can moderate the tumor microenvironment (TME) in response to inflammatory signals. They also include essential information about the immune cell-specific expression and functions of circRNAs in the TME, as well as their roles in inflammatory pathways driving tumorigenesis. The therapeutic potential of circRNAs in exploiting inflammatory responses in cancer represents a new avenue of research. Srinivas et al. explore in detail the roles of lncRNAs in brain development and pathogenesis, including Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration, Huntington's disease, and Parkinson's disease.4Srinivas T. Mathias C. Oliveira-Mateos C. Guil S. Roles of lncRNAs in brain development and pathogenesis: emerging therapeutic opportunities.Mol. Ther. 2023; https://doi.org/10.1016/j.ymthe.2023.02.008Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The authors summarize the most recent mechanistic findings associated with lncRNAs in normal brain function and in neurodevelopmental or neurodegenerative disorders, their use as biomarkers for central nervous system diseases, and their potential utility for therapeutic strategies. In a carefully crafted review, Yuru Zong and colleagues discuss the roles of microRNAs and lncRNAs in the regulation of glucose, fatty acid, and amino acid metabolism that occurs in living organisms and contributes to the pathogeny of cancer and of cardiovascular diseases.5Zong Y. Wang X. Cui B. Xiong X. Wu A. Lin C. Zhang Y. Decoding the regulatory roles of non-coding RNAs in cellular metabolism and disease.Mol. Ther. 2023; https://doi.org/10.1016/j.ymthe.2023.04.012Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Furthermore, they note that some miRNA therapies associated with lipid metabolism and cardiovascular disease are already undergoing clinical evaluation. Finally, Huang et al. provide an overview of the extensive recent literature that explores lncRNA functions in human diseases, including cancer.6Huang L.A. Li C. Yang L. Plumbing mysterious RNAs in "dark genome" for the conquest of human diseases.Mol. Ther. 2023; 31: 1577-1595Abstract Full Text Full Text PDF Google Scholar The authors also discuss future directions for developing promising lncRNA-related treatments, although challenges remain in diagnosis, drug delivery, and immune responses related to lncRNA function. They expand on the concept that lncRNA functional domains are crucial for interactions with other molecules such as DNA, RNA, or proteins. Such knowledge can be essential for the development of efficient therapeutics. These reviews should be useful to those in the field of ncRNAs and those outside the field alike as the authors expertly convey the significance of the latest developments in these large and complex fields of research. Perhaps the most significant potential development in the ncRNA field will be the development of safe and efficient ncRNA therapeutics. We believe that breakthrough therapeutic developments rivalling the effects of Glivec will facilitate the recruitment of young, bright minds to the field to drive further innovation. Altogether, the word of the day for the further advancement of the ncRNA field is creativity!